Breast cancer is the most frequent and the most feared cancer in women in the United States. The incidence of breast cancer has increased slowly and steadily over the past 20 years. A consistent finding in most epidemiological studies has been the protective effect of pregnancy on the incidence of human breast cancer. In animal models the protection afforded by pregnancy can be mimicked by short-term exposure to low doses of estrogens and progestins. The cellular and molecular understanding of the protective effect of hormones is a critical question which is relevant to developing a prevention approach to human breast cancer. The long term goals of this program project are to understand how hormones are used naturally by the organism to prevent the development project are to understand how hormones are used naturally by th organism to prevent the development of breast cancer. The approach described in this Program Project application is unique as it focuses on a limited exposure of low doses of naturally-occurring hormones to permanently decrease the risk of breast cancer development. The Program Project is designed as a multi- disciplinary approach focused on a single model to address a question immediately relevant to prevention of human breast cancer. The model is the hormone (estrogen and progesterone)-induced prevention of N-methyl-N- nitrosourea - induced breast cancer in the inbred Wistar-Furth female at. The Program Project consists of 4 Projects and 3 Core facilities. Project 1 examines the efficacy of short-term low dose hormone treatments, the persistence and the tissue localization of the resistant state. Project 2 examines cell proliferation kinetics in the resistant state and the analysis of nuclear matrix proteins unique to the resistant state. Project 3 examines specific genes unique to the susceptible and resistant state ina the developing gland and the expression and localization of specific mammary developmental genes. Project 4 examines the importance of estrogen and progesterone receptor composition and function to the oncogenic potential of the gland. Each project is dependent upon the experimental and intellectual contributions of the Animal Resources Core and the Microscopy and Molecular Cytochemistry Core. The success of this Program Project depends on the complementary expertise provided by the individual investigators in the areas of tumor biology, reproductive biology, developmental biology, molecular endocrinology and molecular biology. The understanding of the fundamental biological events involved in mammary cell growth and hormone-induced differentiation will provide a rationale for developing new preventive approaches for controlling and reversing the rising tide of human breast cancer.